Chronic hepatitis B (CHB) affects =1.5 million Americans, with Asian-Americans disproportionately affected, and =5000 deaths annually due to cirrhosis and hepatocellular carcinoma. With the availability of effective, well-tolerated HBV treatments, reductions in liver-related deaths are achievable. However, unanswered questions include whether the current target groups for treatment should be expanded, if combinations of drugs are superior to a single drug, whether interferon-containing regimens can modulate a favorable immune response that augments Early (HBe) and Surface (HBs) antigen seroconversion, and what treatment durations and endpoints should optimally be used? The San Francisco HBV Consortium together with other Hepatitis B Research Network (HBRN) investigators has implemented 5 clinical protocols (2 observational studies and 3 clinical trials) and 16 ancillary studies including quality of life, epidemiology, immunology, virology, and genomic. To date 1,875 adults and 375 children are in longitudinal follow-up and the biorepository acquired 191,000 aliquots of serum/plasma, 9,300 aliquots of DNA, 1,800 liver biopsy slides and 120 liver tissue specimens for translational studies. Our study aims for the longitudinal cohort are to identify predictors of disease activation (hepatitis flares, HBV clinica phenotype transitions, HBeAg/HBsAg loss) and progression to cirrhosis, liver failure, and HCC. Special populations under study include pregnant women, those with HDV coinfection, acute hepatitis B and patients with flares. Additionally, we are executing 2 clinical trials, with the primary goal of comparing combination versus monotherapy as first-line therapy The Immune Active (IA) trial is a randomized (1:1) parallel group design trial comparing (i) Tenofovir (TDF) 300 mg daily for 192 weeks (4 years) and (ii) peg-IFN alfa-2a 180g weekly for 24 weeks plus TDF 300 mg daily for 192 weeks in 200 patients with HBeAg positive and negative active CHB. The primary endpoint is HBsAg loss after a finite period of treatment (4 years) and 48 weeks after stopping treatment. The Immune Tolerant (IT) trial is a single arm pilot to evaluate 8 weeks of entecavir (ETV) followed by 40 weeks of both ETV and peg-IFN alfa-2a in 40 adults and 60 children with HBeAg- positive CHB with normal or near normal ALT levels and high serum levels of HBV DNA. The primary endpoint is HBeAg loss and HBV DNA =1,000 IU/mL 48 weeks after stopping therapy. The San Francisco HBV Consortium further proposes to explore the role for vitamin D status in shaping the clinical phenotypes, immunologic transitions and treatment outcomes of adult and pediatric patients with chronic hepatitis B.